Journal
NEUROCHEMISTRY INTERNATIONAL
Volume 52, Issue 6, Pages 990-1001Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2007.10.012
Keywords
striatal dopamine depletion; MPP+-induced (OH)-O-center dot generation; ferrous citrate; experimental Parkinson's disease; oxidative stress; neuroprotective therapy; free radical scavenger; endogenous antioxidant molecules; antioxidant enzymes
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The neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7-NI) is neuroprotective against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Monoamine oxidase (MAO)-B inhibitory action partially contributes to this effect. We tested the hypothesis that 7-NI could be a powerful hydroxyl radical ((OH)-O-center dot) scavenger, and interferes with oxidative stress caused by MPTP. We measured (OH)-O-center dot, reduced glutathione (GSH), as well as superoxide dismutase (SOD) and catalase activities in the nucleus caudatus putamen and substantia nigra of Balb/c mice following MPTP and/or 7-NI administration. The nNOS inhibitor caused dose-dependent inhibition in the production of (OH)-O-center dot in (i) Fenton-like reaction employing ferrous citrate in a cell-free system in test tubes, (ii) in isolated mitochondrial preparation in presence of MPP+, and (iii) in the striatum of mice systemically treated with MPTP. An MPTP-induced depletion of GSH in both the nuclei was blocked by 7-NI, which was dose-dependent (10-50 mg/kg), but independent of MAO-B inhibition. The nNOS-mediated recovery of GSH paralleled attenuation of MPTP-induced depletion of striatal dopamine. MPTP-induced increase in the activities of striatal or nigral SOD and catalase were significantly attenuated by 7-NI treatment. These results suggest potent antioxidant action of 7-NI in its neuroprotective effects against MPTP-induced neurotoxicity. (C) 2007 Elsevier Ltd. All rights reserved.
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